One-pot synthesis of 7-aryl-octahydroazonino[5,4-b]indoles based on the fragmentation of indolizino[8,7-b]indoles and the insertion of indoles and 3,4,5-trimethoxyphenol

Article abstract of DOI:10.1055/s-0028-1087565

A series of 7-aryl-octahydroazonino[5,4-b]indoles were prepared in one pot via a three component reaction from indolizino[8,7-b]indoles, α-chloroethyl chloroformate (ACE-Cl) and activated arenes such as indoles and 3,4,5-trimethoxyphenol. Georg Thieme Ver

Full text of DOI:10.1055/s-0028-1087565

LETTER
581
One-Pot Synthesis of 7-Aryl-Octahydroazonino[5,4-b]indoles Based on the
Fragmentation of Indolizino[8,7-b]indoles and the Insertion of Indoles and
3,4,5-Trimethoxyphenol
O
ne-Pot Synthesis
e
of 7-Aryl-O
m
ctahydroazonino[5
o
,4-
b
]
indolessthenes Fokas,*1 James A. Hamzik2
Department of Chemistry, ArQule, Inc., 19 Presidential Way, Woburn, MA 01801, USA
E-mail: dfokas@cc.uoi.gr
Received 23 October 2008
arene to the newly generated azonino ring (Figure 1). Al-
though the insertion of anilines has been described,6 the
use of other activated arenes such as indoles and oxygen-
ated aromatics has not yet been explored. Herein, we wish
to report the results of our studies pertaining to the one-pot
synthesis of 7-aryl-octahydroazonino[5,4-b]indoles with
general structure 2, resulting from the ACE-Cl-mediated
fragmentation of indolizinoindole 3 (R1 = H, CO2Me) ac-
companied by the insertion of indoles and 3,4,5-tri-
methoxyphenol (Scheme 1).
Abstract: A series of 7-aryl-octahydroazonino[5,4-b]indoles were
prepared in one pot via a three component reaction from indolizi-
no[8,7-b]indoles, a-chloroethyl chloroformate (ACE-Cl) and acti-
vated arenes such as indoles and 3,4,5-trimethoxyphenol.
Key words: indolizino[8,7-b]indole, fragmentation, arene, inser-
tion, 7-aryl-octahydroazonino[5,4-b]indole
Inspired by early model studies on vinblastine’s hypothet-
ical mechanism of action,3 we turned our attention to the
design of azonino[5,4-b]indoles in the hope to identify
new cytotoxic agents. We surmised that a series of octa-
hydroazonino[5,4-b]indoles 1 with an activated aryl
group at the C7 carbon center might exhibit some of vin-
blastine’s structural features required for cytotoxic activi-
ty. If we were to test this hypothesis, then access to a
diverse set of the target compounds would require the syn-
thesis of 7-aryl-octahydroazonino[5,4-b]indoles 2, con-
taining an activated aryl group at the C7 carbon center as
well as a secondary N3 nitrogen center. Compound 2
would in turn result from the fragmentation of tertiary
amine 3 (Figure 1).
HO
Et
N
N
Et
N
OAc
H
H
H
CO2Me
MeO2C
N
OH
MeO
Me
vinblastine
R2
H
N
N
3
3
The alkyl chloride induced quaternization of indolizi-
no[8,7-b]indole 3 (R1 = Ar) followed by reductive cleav-
age of the b-tetrahydrocarboline (b-THC) ring, could
provide immediate entry to a number of 7-aryl-octahydro-
azonino[5,4-b]indoles 1 (R1 = H, R2 = alkyl, Ar = Ph, fu-
ryl, thienyl).4 However, due to the small number of lower
alkyl halides utilized in the quaternization of indolizinoin-
dole 3 (R1 = Ar), this fragmentation strategy could only
lead to a restricted number of 3-alkyl-azonino[5,4-b]in-
doles. Dealkylation of the resulting 3-alkyl substrate to
the corresponding azonine 2 (R1 = H) may serve as an al-
ternative method, which could offset this limitation, but
this approach may prove cumbersome. Most importantly,
this strategy lacks the ability to introduce the desired fea-
tures of the target compounds, namely a C7 carboxymeth-
yl group as well as an activated aryl group.
1
12
9
N
7
7
8
N
H
N
H
N
H
R1
R1
R1
Ar
2 R1 = H, CO2Me
Ar
1 R1 = H, CO2Me
3
Figure
scaffolds
1
7-Aryl-octahydroazonino[5,4-b]indoles from b-THC
Treatment of indolizinoindoles 3a and 3b with ACE-Cl
could induce cleavage of the b-THC ring, providing a
transient iminium ion which could generate adducts 4a
and 4b, respectively, when trapped in the presence of an
indole. Subsequent cleavage of the labile a-chloroethyl
carbamate7 would afford azonino[5,4-b]indoles 5 and 6
(Scheme 1). Indeed, when substrates 3a8 and 3b9 were
treated at room temperature with ACE-Cl (1.2 equiv) in
dichloroethane (DCE),10 in the presence of an indole (1.1
equiv), the corresponding indole adducts 4a and 4b were
produced. Addition of MeOH to the crude reaction mix-
ture, followed by heating at 50 °C for one hour, led to car-
bamate cleavage and formation of 7-(1H-indol-3-yl)-
octahydroazonino[5,4-b]indoles 5 and 6, respectively.
Access to the desired octahydroazonino[5,4-b]indole 2
would result from indolizino[8,7-b]indole 3 (R1 = H,
CO2Me) via a chloroformate-induced fragmentation5 of
the b-THC ring, followed by insertion of an activated
SYNLETT 2009, No. 4, pp 0581–0584
x
x.
x
x.
2
0
0
9
A number of indoles with various substitution patterns
were found to undergo an insertion reaction, resulting in
Advanced online publication: 16.02.2009
DOI: 10.1055/s-0028-1087565; Art ID: G35208ST
© Georg Thieme Verlag Stuttgart · New York

582
D. Fokas, J. A. Hamzik
LETTER
Cl
O
N
O
H
N
N
R2
N
H
R1
R4
R2
H
R1
R4
Cl
N
R3
O
N
N
R3
O
5 R1 = H
4a R1 = H
Cl
O
6 R1 = CO2Me
4b R1 = CO2Me
N
MeOH
50 °C
O
Cl
ArH
N
R1
DCE, r.t.
N
H
R1
H
N
H
Cl
O
O
N
3a R1 = H
3b R1 = CO2Me
OH
N
H
H
OH
OH
OMe
MeO
OMe
N
H
R4
R2
R1
ArH =
9
N
OMe
OMe
MeO
MeO
OMe
R3
H
OMe
N
7a R1 = H
7b R1 = CO2Me
OMe
OMe
OMe
N
O
H
OR
O
O
N
10
OMe
OMe
OMe
N
H
O
O
8
R = CH(Cl)Me
11 R = 4-ClC6H4
Scheme 1 Access to 7-aryl-octahydroazonino[5,4-b]indoles through the fragmentation of indolizino[8,7-b] indoles and the insertion of acti-
vated arenes
azonines 5 (Table 1, entries 1–7) and 6 (Table 1, entries substrate 3b under the same reaction conditions. Attempts
10–15) in moderate yields (21–46%). Attempts to im- to generate compound 7b were not fruitful and spirolac-
prove the reaction yields utilizing an excess of ACE-Cl tone 8 was obtained as the sole product, presumably via an
(2–3 equiv) and indole (2–3 equiv) were not fruitful given intramolecular lactonization reaction between the C7 car-
the inability to drive the fragmentation of indolizino- boxymethyl group and the neighboring phenolic hydrox-
indoles 3a and 3b to completion. Both N–H and N-alkyl yl. Similarly, spirolactone 11 resulted from the reaction of
indoles were shown to be reactive, with the alkylation oc- 3b with 4-chlorophenyl chloroformate and 3,4,5-tri-
curring exclusively at the b-indolic carbon. The presence methoxyphenol.12 Subsequently, cleavage of the crude
of an electron-withdrawing carboxylate at the 2-position carbamates 7a and 8 with MeOH at 50 °C afforded 3,4,5-
of the indole rendered the indole inactive and failed to trimethoxy-2-{octahydroazonino[5,4-b]indol-7-yl}phe-
give the desired product (Table 1, entry 8). However, the nol 9 (Table 1, entry 16) and 4¢,5¢,6¢-trimethoxy-hexahy-
presence of a bulky phenyl group at the 2-position did not dro-2H-spiro{azonino[5,4-b]indole-7,3¢-[1]benzofuran}-
seem to affect the indole reactivity, as was witnessed by 2¢-one 10 (Table 1, entry 17), respectively.
the formation of 5b (Table 1, entry 2). Surprisingly, the 5-
methoxy-2-methyl-indole failed to generate the desired
product, presumably due to a competitive side reaction
with ACE-Cl (Table 1, entry 9).
Furthermore, we found that treatment of 3a with (Boc)2O
(1.2 equiv) as the acylating agent,13 in the presence of N-
methyl indole as well as 2-(4-fluoro)phenyl indole (1.1
equiv), allowed access to the corresponding N-Boc-
Amongst a series of oxygenated aromatics being tested,11 protected azonino[5,4-b]indoles 12 and 13, respectively
3,4,5-trimethoxyphenol was that found to insert to the (Scheme 2). In contrast, ester substrate 3b failed to under-
azonino nucleus during the fragmentation of indolizino- go a ring expansion under the same reaction conditions
indoles 3a and 3b (Scheme 1). Indeed, treatment of 3a and starting material was recovered. Should cleavage of
with ACE-Cl (1.2 equiv), in the presence of 3,4,5-tri- the tert-butyl carbamates 12 and 13 occur under standard
methoxyphenol (1.1 equiv), gave phenol adduct 7a. How- acidic conditions, it would serve as an alternative method
ever, spirolactone 8, instead of ester 7b, was formed from for the synthesis of azonines 5a and 5b, respectively.
Synlett 2009, No. 4, 581–584 © Thieme Stuttgart · New York

LETTER
One-Pot Synthesis of 7-Aryl-Octahydroazonino[5,4-b]indoles
583
H
N
Boc
H
N
••
N
H+
(Boc)2O
DCE, r.t.
– indole
R2
N
3a
5
H
••
N
N
H
H
R4
N
H
H
N
R2
H
H
R2
N
R3
N
N
I
3a
II
R1
R1
Scheme 3 Acid-induced decomposition of azonino[5,4-b]indole 5
12 R1 = Me, R2 = H, 48%
13 R1 = H, R2 = 4-FC6H4, 46%
The (Boc)2O-induced fragmentation of indolizinoindoles
might provide a complementary approach for the synthe-
sis of several azonino[5,4-b]indoles. However, the lack of
reactivity of ester substrate 3b, coupled with the acid-
labile nature of azonines 5, kept us from pursuing this
scheme any further. The chemistry depicted in Scheme 1
illustrates the one-pot synthesis of new versatile azoni-
no[5,4-b]indole scaffolds from a common intermediate
through a key-bond-breaking reaction, followed by the in-
sertion of an aromatic nucleophile. Although the synthesis
of these compounds is achieved in moderate yields, fur-
ther elaboration of the secondary azonine nitrogen center
as well as the C7 carboxymethyl group may lead to new
chemotypes and thus enhance the search for new
bioactive16 azonino[5,4-b]indoles. The methods described
here could also enable the high-throughput solution-phase
synthesis of a diverse set of azonino[5,4-b]indoles desir-
able for drug discovery. The preparation of such screening
libraries will be communicated in due course.
Scheme 2 N-Boc-azonino[5,4-b]indoles via the fragmentation of 3a
with (Boc)2O
Table 1 One-Pot Synthesis of 7-Aryl-octahydroazonino[5,4-b]-
indoles via a Three-Component Reaction
Entry Compound R1
R2,c
R3 R4
Yield
(%)a
1
2
5a
5b
5c
5d
5e
5f
H
H
Me
H
H
45
H
H
4-FC6H4 30
3
H
H
H
Me
H
41
38
40
43
42
0b
4
H
5-F
7-Me
4-MeO
7-Cl
H
H
5
H
H
H
6
H
Me
H
H
7
5g
5h
5i
H
H
8
H
H
CO2Et
Me
H
9
H
5-MeO
H
H
0b
Acknowledgment
10
11
12
13
14
15
16
17
6a
6b
6c
6d
6e
6f
CO2Me
CO2Me
Me
H
42
44
21
39
38
40
45
31
The authors thank Dr. Zhimin Wang for the preparation of com-
pounds 3a and 3b. The authors also thank ArQule’s Analytical
Department for the mass spectral analysis of the compounds descri-
bed in the manuscript.
H
H
CO2Me 4-Cl
CO2Me 5-Cl
H
H
H
Me
References and Notes
CO2Me
CO2Me 6-MeO
H
Me Me
(1) Current address: Department of Materials Science and
Engineering, University of Ioannina, 45110 Ioannina,
Greece; +30 (26510)97034; dfokas@cc.uoi.gr.
(2) Current address: Millipore Corporation, 80 Ashby Road,
Bedford, MA 01730, USA.
(3) Magnus, P.; Ladlow, M.; Elliott, J. J. Am. Chem. Soc. 1987,
109, 7929.
(4) (a) Houlihan, W. J.; Manning, R. E. US 3,478,051, 1969.
(b) Herbst, D. R.; Smith, H. US 3,943,148, 1976.
(c) Herbst, D.; Rees, R.; Hughes, G. A.; Smith, H. J. Med.
Chem. 1966, 9, 864.
H
–
H
–
9
H
–
–
–
10
–
–
a Isolated yields of purified products. All compounds produced satis-
factory 1H NMR, 13C NMR, and mass spectra.14,
b Trace amounts of product were detected by LC–MS.
c Numbering is based on the starting material indole.
(5) (a) Calverley, M. J. J. Chem. Soc., Chem. Commun. 1981,
1209. (b) Calverley, M. J.; Harley-Mason, J.; Quarrie, S. A.;
Edwards, P. D. Tetrahedron 1981, 22, 1635. (c) Schill, G.;
Priester, C. U.; Windhövell, U. F.; Fritz, H. Helv. Chim. Acta
1986, 69, 438.
(6) (a) Magnus, P.; Ladlow, M.; Elliott, J.; Kim, C. S. J. Chem.
Soc., Chem. Commun. 1989, 518. (b) Takahashi, T.; Inoue,
H.; Horigome, M.; Momose, K.; Sugita, M.; Katsuyama, K.;
Suzuki, C.; Nagai, S.; Nagase, M.; Nakamaru, K. EP
535529, 1997.
When carbamates 12 and 13 were treated with a slight ex-
cess of TFA in DCE (6–8 equiv) or HCl (2 equiv) in diox-
ane, they failed to produce azonines 5a and 5b,
respectively. Indeed, formation of 3a was observed in all
instances. The labile nature of 5a and 5b, when in the
presence of acid, may account for the rise of 3a.15 The
mechanism for the formation of 3a may presumably in-
volve protonation of 5 at the pendant indole to give indo-
lium intermediate I. Indole release from I could generate
iminium intermediate II, which could then be converted
into indolizinoindole 3a (Scheme 3).
(7) Olofson, R. A.; Martz, J. T.; Senet, J.-P.; Piteau, M.;
Malfroot, T. J. Org. Chem. 1984, 49, 2081.
(8) Corsano, S.; Algieri, S. Ann. Chim. 1960, 50, 75.
Synlett 2009, No. 4, 581–584 © Thieme Stuttgart · New York

584
D. Fokas, J. A. Hamzik
LETTER
(9) Fokas, D.; Wang, Z. Synth. Commun. 2008, 38, 3816.
(10) Reaction was found to work equally well in other chlorinated
solvents such as CH2Cl2 and CHCl3.
Compound 6a: 1H NMR (400 MHz, CDCl3): d = 9.70–8.80
(br s, 1 H), 7.42 (d, 1 H, J = 8.4 Hz), 7.35–7.17 (m, 5 H), 7.11
(t, 1 H, J = 7.7, 7.0 Hz), 7.07 (s, 1 H), 6.98 (t, 1 H, J = 7.7,
7.3 Hz), 3.76 (s, 3 H), 3.73 (s, 3 H), 3.50–3.25 (m, 6 H), 3.15
(m, 1 H), 3.00 (br s, 1 H), 2.85 (s, 1 H), 2.00 (br s, 1 H), 1.90
(s, 1 H). 13C NMR (75.4 MHz, CDCl3): d = 174.5, 137.6,
134.8, 133.9, 127.8, 125.8, 122.7, 122.2, 120.1, 119.9,
117.9, 115.7, 111.6, 110.0, 109.8, 109.4, 53.2, 51.7, 46.8,
44.6, 33.2, 32.4, 23.6, 22.4. MS (ES+): m/z calcd for
C25H27N3O2: 401.21; found: 402.19 [M + H]+.
(11) Attempts to achieve the same insertion reaction with 1,2
dimethoxybenzene as well as other less oxygenated phenols
such as phenol, 4-methoxyphenol, 4-methylphenol, and
4-bromophenol, failed to generate the desired products.
(12) Compound 11 was isolated in 47% yield after purification by
preparative TLC with EtOAc–hexanes (1:4) as the eluent:
1H NMR (400 MHz, CDCl3): d = 7.48 (d, 2 H, J = 7.0 Hz),
7.24–7.02 (m, 5 H), 6.94 (d, 1 H, J = 7.0 Hz), 6.75 (d, 1 H,
J = 7.4 Hz), 6.53 (s, 1 H), 4.10 (m, 1 H), 3.87 (s, 3 H), 3.79
(s, 3 H), 3.74 (s, 3 H), 3.64 (m, 2 H), 3.38 (m, 3 H), 2.80 (br
s, 1 H), 2.20 (br s, 2 H), 2.10 (s, 1 H). MS (ES+): m/z calcd
for C31H29ClN2O7: 576.17; found: 577.10 [M + H]+.
(13) For the reaction of 3a with carboxylic acid anhydrides, see:
(a) Schill, G.; Loewer, H.; Priester, C. U.; Windhöevel,
U. F.; Fritz, H. Tetrahedron 1987, 43, 3729. (b) Harley-
Mason, J.; Atta-ur-Rahman Tetrahedron 1980, 36, 1057.
(c) Foster, G. H.; Harley-Mason, J.; Waterfield, W. R.
J. Chem. Soc., Chem. Commun. 1967, 21.
(14) Typical Experimental Procedure for the Synthesis of
7-Aryl-octahydroazonino[5,4-b]indoles 5, 6, 9, and 10
To a solution of indolizinoindole 3 (0.1 mmol) and aromatic
nucleophile (1.1 equiv) in DCE at r.t., a-chloroethyl
chloroformate (1.2 equiv) was added. The reaction mixture
was stirred at r.t. overnight and then treated with MeOH
(1 mL) at 50 °C for 1 h. The reaction mixture was then
concentrated and the crude product was purified by silica gel
column chromatography with CH2Cl2–MeOH (from 100:0
to 90:10) as the eluent.
Compound 9: 1H NMR (400 MHz, CDCl3): d = 9.17 (br s,
1 H), 7.35 (d, 1 H, J = 7.4 Hz), 7.25 (d, 1 H, J = 6.7 Hz), 7.07
(m, 2 H), 6.56 (s, 1 H), 4.97 (d, 1 H, J = 9.0 Hz), 3.98 (s, 3
H), 3.80 (s, 3 H), 3.76 (s, 3 H), 3.50–3.30 (m, 3 H), 3.25–2.95
(m, 3 H), 2.78 (br s, 1 H), 2.10 (br s, 1 H), 1.98 (s, 1 H), 1.78
(br s, 1 H). 13C NMR (100.6 MHz, CDCl3): d = 152.9, 151.7,
150.6, 139.9, 136.4, 135.9, 129.6, 127.1, 122.1, 119.6,
117.5, 115.5, 111.3, 98.6, 62.0, 61.2, 56.1, 47.6, 46.2, 33.5,
31.7, 25.4, 21.5. MS (ES+): m/z calcd for C23H28N2O4:
396.20; found: 397.04 [M + H]+.
Compound 10: 1H NMR (400 MHz, CDCl3): d = 9.80 (br s,
1 H), 7.66 (br s, 1 H), 7.46 (d, 1 H, J = 7.4 Hz), 7.23–7.11
(m, 3 H), 6.60 (s, 1 H), 3.91 (s, 3 H), 3.82 (s, 3 H), 3.79 (s, 3
H), 3.70 (m, 1 H), 3.58 (br s, 2 H), 3.38 (s, 3 H), 3.17–2.82
(br s, 1 H), 2.80–2.50 (br s, 1 H), 2.35 (s, 1 H), 2.20 (s, 1 H).
13C NMR (75.4 MHz, CDCl3): d = 176.1, 156.0, 150.2,
148.9, 138.8, 135.1, 129.2, 128.5, 123.4, 120.6, 118.1,
113.5, 112.1, 111.1, 92.2, 61.4, 61.1, 56.7, 47.1, 43.9, 36.6,
33.0, 23.9, 22.0. MS (ES+): m/z calcd for C24H26N2O5:
422.18; found: 423.04 [M + H]+.
(15) Indolylazonines 5 were found to be acid sensitive. They
gradually decomposed when samples were dissolved in
CDCl3, presumably by traces of HCl present in the solvent.
In contrast, no decomposition was observed when samples
were dissolved in CD3OD and stored at r.t. for over two
weeks. Indolylazonines 6 were found to be stable when
dissolved in CDCl3.
(16) A series of 7-alkyl and 7-aryl-octahydroazonino[5,4-
b]indoles have exhibited a wide range of biological
properties as CNS stimulants, antidepressants, anti-
inflammatories, diuretics, and anti-ulcer agents. For more
information, see ref. 4 and 6b.
Spectroscopic Data for Selected Compounds
Compound 5g: 1H NMR (400 MHz, CD3OD): d = 7.52 (m,
1 H), 7.26 (s, 1 H), 7.22–7.17 (m, 2 H), 7.07–7.02 (m, 3 H),
6.80 (t, 1 H, J = 7.8 Hz), 4.75 (t, 1 H, J = 9.0, 7.0 Hz), 3.55–
3.38 (m, 3 H), 3.30–3.20 (m, 2 H), 3.10 (m, 1 H), 2.45 (m,
2 H), 1.93 (m, 1 H), 1.65 (m, 1 H). 13C NMR (100.6 MHz,
CD3OD): d = 138.1, 136.5, 134.1, 128.7, 127.6, 122.9,
121.3, 120.9, 119.5, 119.0, 117.9, 117.5, 117.2, 116.5,
111.0, 106.5, 46.9, 44.9, 33.9, 30.8, 23.7, 20.8. MS (ES+):
m/z calcd for C22H22ClN3: 363.15; found: 364.08 [M + H]+.
Synlett 2009, No. 4, 581–584 © Thieme Stuttgart · New York

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